Transcription factors are proteins that bind to special regions of DNA called enhancers, so as to regulate gene expression. Some transcription factors activate gene expression, while others repress it. Gene expression level is like the volume of a radio; some transcription factors turn the volume up, while others turn it down.
Scientists have investigated how activation and repression work and how to predict the level of gene expression. In the same way, by turning the volume knob of a radio, it is possible to know how loud or soft the music will be and to regulate it--except that, in this case, each transcription factor has its own volume knob all acting on the same speaker. The challenge is to understand how they all work together to produce the right volume.
Published in Nature Genetics, this study has important implications in cellular and developmental biology, with potential applications in stem cell reprogramming and regenerative medicine.
Researchers have developed a mathematical model that shows how to predictably tune gene expression. This was validated experimentally using a technique for adjusting gene expression in fruit fly embryos.
Scientists applied a new mathematical model that does not require information about the number and position of transcription factors binding to the enhancer, which would be like knowing the inner workings of the radio. Instead, the model correctly predicts the final volume only by knowing how the volume knobs are turned. These predictions were tested experimentally using artificial transcription factors that activate and repress gene expression with different strengths.
Scientists worked with fruit fly (Drosophila melanogaster) early stage embryos. The mathematical model shows that expression of genes that determine segmentation of the fruit fly body from head to tail is tunable. Experimental results match the model's prediction, showing that artificial activators and repressors can increase and decrease gene expression gradually in a way that is controllable and reproducible. This is like attaching yet another volume knob to the radio and finding that it works in concert with the existing knobs. Beyond gene expression level, the model was also able to predict in which location in the embryo, for example ventral or dorsal, the gene would be expressed.
This study also shows that enhancers can acquire new activators and repressors quite flexibly. "We are moving away from having to use an on/off model of gene expression to understand how cell types are specified. Advances in quantitative biology at the single-cell level, like quantitative imaging and RNA sequencing, together with mathematical models, now give biologists the tools they need to delve into the intricacies of gene expression tuning and to predictably manipulate the cell," concludes the author.